Regardless of the initial insult, human chronic kidney disease (CKD) is characterized by progressive destruction of the renal parenchyma and the loss of functional nephrons which ultimately lead to end stage renal failure (ESRF). CKD represents a worldwide concern: in the USA, 102,567 patients began dialysis in 2003 (341 patients/year per/million) (1), and similar rates were found in developing countries and in particular ethnic groups (2). However, these numbers are a small fraction of the millions of patients who are thought to have some degree of renal impairment. In the United States the prevalence of chronically reduced kidney function is 11% of adults (3). Understanding the pathophysiology of CKD progression is, therefore, a key challenge for medical planning.
The mechanisms of CKD progression are poorly understood. It has been shown that reduction of the number of functional nephrons triggers molecular and cellular events promoting compensatory growth of the remaining ones (4). In some cases, this compensatory process becomes pathological with the development of renal lesions and ESRF. Although the pathophysiology of compensation and progression is complex, unregulated proliferation of glomerular, tubular and interstitial cells may promote the development of glomerulosclerosis, tubular cysts, and interstitial fibrosis (5-7). The molecular programs that control this cascade of events are largely unknown.
Attempts to dissect the molecular basis of CKD have been facilitated by the development of several experimental models of renal deterioration. Among these, the remnant kidney model is a mainstay, since nephron reduction characterizes the evolution of most human CKD. Consequently, this model recapitulates many features of human CKD, including hypertension, proteinuria, glomerular and tubulointerstitial lesions. Over the last fifty years, this model has led to the discovery of critical pathways and, more importantly, to the design of therapeutic strategies to slow down the progression of CKD, such as the widely clinically used renin-angiotensin inhibitors (8).
More recently, studies in different mouse strains have highlighted the importance of genetic factors in the evolution of experimental nephron reduction (9-11). We previously showed that the course and extent of renal lesions following nephron reduction vary significantly between two mouse strains: whereas the FVB/N mice develop severe lesions, the (C57BL/6xDBA2)F1 (hereafter denoted B6D2F1) undergoes compensation alone (12). Moreover, we observed that the development of renal lesions paralleled the extent of cell proliferation (12). In fact, once the compensatory growth is achieved, a second wave of cell proliferation occurs only in the FVB/N strain.
There is a need in the art for a reliable biomarker which allows the prediction of the progression of CKD in particular in human patients suffering from said disease as well as relevant treatments for preventing or treating CKD.